Time-Resolved Quantum Magnetic Force Spectroscopy for Protein Bonding and Drug Screening

This proposal aims to develop time-resolved quantum magnetic force spectroscopy (QMFS) that employs a quantum magnetometer integrated with in situ acoustic force for the first time. It will provide direct measurements of magnetically labeled biological processes with unprecedented molecular specificity using acoustic force amplitudes, thereby resolving complex protein bonds. The innovative engineering design will also enable a new concept of single-shot force spectroscopy, in which all biomolecular bonds can be identified by a single force application, facilitating broader biological applications. The new technique will represent a fundamentally different approach to studying molecular recognition, benefiting both basic research and society. The successful outcome will enhance the current knowledge base for viral targeting and accelerate the development of new drugs. The device to be developed will also provide a new avenue for researchers to investigate noncovalent protein bonds, the dominant bonding mechanism in biology. The interdisciplinary research will offer unique opportunities for students with different backgrounds and broad interests, as it contains magnetic, mechanical, optical, electrical, chemical, and biological components. Therefore, different projects can be tailored to stimulate students’ motivation and imagination, including undergraduate and high school researchers. Funding this proposal will also enhance teaching and serve the science and engineering community: a new graduate-level course on analytical spectroscopy techniques is being developed; the impact on society will be realized through the many public science events held annually in one of the country's largest metropolitan areas. This proposal offers three major innovative engineering approaches, as reflected in its three specific aims, to research fields including quantum sensing, magnetometry, and force spectroscopy. First, direct integration between a quantum sensor of any type and a mechanical force of any form has not been realized. QMFS will be the first technique to combine a quantum sensor and a piezoelectric element to generate force at the same location, enabling time-resolved monitoring of biological functions. Second, the implementation of new sample designs introduces a much-needed avenue for removing nonspecific interactions, the main source of noise in force spectroscopy. It also enables flexible delivery of the required biological reagents in accordance with the experimental sequence, quantities, and reaction times. Therefore, this technical innovation will enable the study of complex biological systems. Third, QMFS will enable single-shot force spectroscopy that reveals all molecular bonds after a single force application, a completely new concept in the field of force spectroscopy, which comprises more than five major techniques. These unique advantages will thus provide force spectra that indicate complex molecular recognition and enable high-confidence predictions of drug interference. On the fundamental biological science front, the research will produce the much-desired but currently unavailable data on the specificity of molecular recognition with sub-piconewton resolution, which is at least twenty times more precise than other force-based techniques. Measurements in a live-cell setting will yield the most biologically relevant data, a level not achieved in previous research. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.